The present invention relates to novel substituted oxindoles and related compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds as inhibitors of phosphodiesterase ("PDE") type IV. The compounds of this invention are useful in the treatment of AIDS, asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases. This invention also relates to pharmaceutical compositions containing these compounds and to methods of inhibiting the action of phosphodiesterase type IV.
Since the recognition that cyclic adenosine monophosphate ("cAMP") is an intracellular second messenger (E. W. Sutherland and T. W. Rall, Pharmacol. Rev., 1960, 12, 265), inhibition of phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. Distinct classes of phosphodiesterases have been recognized (J. A. Beavo and D. H. Reifsnyder, TIPS, 1990, 11, 150) and their selective inhibition has led to improved drug therapies (C. D. Nicholson, R. A. Challiss, and M. Shahid, TIPS, 1991, 12, 19). It has been claimed that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verghese, et al., J. Mol. Cell Cardiol., 1989, 12 (Supp. II), S 61) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds. S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag).
Certain pyrimidone compounds have been described as antidepressants in EP 0 247 725 A2, published Dec. 2, 1987. Certain pyrimidone compounds have been described as useful against asthma and certain skin disorders in WO 91/07178 published May 30, 1991.
The following documents relate to inhibitors of phosphodiesterase type IV: WO 87/06576, published Nov. 5, 1987; WO 91/15451, published Oct. 17, 1991; WO 91/16303, published Oct. 31, 1991; WO 92/00968, published Jan. 23, 1992; WO 92/07567, published May 14, 1992; WO 92/12961, published Aug. 6, 1992; EP 0 428 313 A2, published May 22, 1991; EP 0 442 204 A2, published Aug. 21, 1991; EP 0 470 805 A1, published Feb. 12, 1992; EP 0 473 963 A1, published Mar. 11, 1992; EP 0 497 564 A1, published Aug. 5, 1992; EP 0 511 865 A1, published Nov. 4, 1992; and EP 0 303 418 A2, published Feb. 15, 1989. The following documents relate to inhibitors of phosphodiesterase type IV in non-pulmonary/nonallergic uses: U.S. Pat. No. 4,582,834, issued Apr. 15, 1986; U.S. Pat. No. 4,971,959, issued Nov. 20, 1990; U.S. Pat. No. 5,077,290, issued Dec. 31, 1991; DE 3742716 A1, published Jun. 22, 1989; and DE 4027592 A1, published Mar. 5, 1992.
All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties.